• Posted June 21, 2023

Could Loss of the Y Chromosome Help Speed Cancers in Men?

It's common knowledge that loss is a part of male aging — loss of hair, loss of muscle tone, loss of vision or hearing.

But men growing older also start losing the very thing that makes them biological males, their Y chromosome, and that can leave them more vulnerable to cancer, a new study says.

The loss of the Y chromosome can help cancer cells evade detection by the body's immune system, according to researchers from Cedars-Sinai Medical Center, in Los Angeles.

Specifically, it results in more aggressive bladder cancer among men, the study authors reported June 21 in the journal Nature.

“This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system's response to cancer,” said researcher Dr. Dan Theodorescu, director of Cedars-Sinai Cancer.

“We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively,” Theodorescu said in a medical center news release.

It's not all bad news, however. Bladder cancers driven by the loss of the Y chromosome also were more vulnerable to immune checkpoint inhibitors, which are drugs that enhance the body's ability to target and destroy tumor cells, the researchers explained.

Each human cell normally has one pair of sex chromosomes. Men's cells have one X and one Y chromosome, while women have two X chromosomes.

Y may disappear with aging

However, aging men can lose the Y chromosome from some cells during normal cell division.

Investigators have found the Y chromosome missing from some white blood cells in about 40% of 70-year-old men and 57% of 93-year-olds, according to Montefiore Medical Center in New York City. In some older men, more than 4 out of 5 white blood cells can lack a Y chromosome.

Loss of the Y chromosome has been observed in several cancer types in men, including 10% to 40% of bladder cancers, Cedars-Sinai researchers said in background notes. It has also been associated with heart disease and Alzheimer's disease.

The Y chromosome contains the blueprints for certain genes. The Cedars-Sinai research team studied the way these genes are expressed in normal cells in the bladder lining, and used that to develop a scoring system that could measure the loss of the Y chromosome in bladder cancer.

The investigators then reviewed data on two groups of men with invasive bladder cancer. One group had their bladders removed but were not treated with an immune checkpoint inhibitor, while the other group received the immunotherapy.

Patients with loss of the Y chromosome had a poorer prognosis in the first group and much better overall survival rates in the latter, the findings showed.

To figure out why this happens, the team performed lab experiments involving bladder cancer cells in mice.

The researchers found that mouse tumor cells lacking the Y chromosome grew at a much faster rate than did tumors with the intact Y chromosome.

However, this only happened in mice with intact immune systems. In mice missing a type of immune cell called T-cells, tumors with and without the Y chromosome grew at the same rate.

“The fact that we only see a difference in growth rate when the immune system is in play is the key to the ‘loss-of-Y' effect in bladder cancer,” Theodorescu said. “These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.”

A silver lining

Based on all of this, Theodorescu and his colleagues also concluded that tumors missing the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint inhibitors.

This immunotherapy, one of the two mainstay bladder cancer treatments available to patients today, reverses T-cell exhaustion and prompts the immune system to fight the cancer.

"Fortunately, this aggressive cancer has an Achilles' heel, in that it is more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors,” said co-lead researcher Hany Abdel-Hafiz, an associate professor at Cedars-Sinai Cancer.

Preliminary data not yet published shows that loss of the Y chromosome can also make prostate cancers more aggressive, Theodorescu said.

“Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumor cells have developed to evade the immune system and survive in multiple organs,” said Shlomo Melmed, dean of the medical faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”

Further research is needed to better understand the genetic connection between loss of the Y chromosome and T-cell exhaustion, the study authors noted.

“If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “T-cell exhaustion can be partially reversed with checkpoint inhibitors, but if we could stop it from happening in the first place, there is much potential to improve outcomes for patients.”

While women do not have a Y chromosome, Theodorescu said these findings could have implications for them as well. The Y chromosome contains a set of related genes on the X chromosome, and these might play a role in both women and men.

“Awareness of the significance of Y chromosome loss will stimulate discussions about the importance of considering sex as a variable in all scientific research in human biology,” Theodorescu said. “The fundamental new knowledge we provide here may explain why certain cancers are worse in either men or women, and how best to treat them. It also illustrates that the Y chromosome does more than determine human biologic sex.”

More information

The U.S. National Cancer Institute has more about immune checkpoint inhibitors.

SOURCE: Cedars-Sinai Medical Center, news release, June 21, 2023